An Iron‐Catalyzed Route to Dewar 1,3,5‐Triphosphabenzene and Subsequent Reactivity

Abstract The application of an alkyne cyclotrimerization regime with an [Fe(salen)]2‐μ‐oxo (1) catalyst to triphenylmethylphosphaalkyne (2) yields gram‐scale quantities of 2,4,6‐tris(triphenylmethyl)‐Dewar‐1,3,5‐triphosphabenzene (3). Bulky lithium salt LiHMDS facilitates a rearrangement of 3 to the 1,3,5‐triphosphabenzene valence isomer (3′), which subsequently undergoes an intriguing phosphorus migration reaction to form the ring‐contracted species (3′′). Density functional theory calculations provide a plausible mechanism for this rearrangement. Given the stability of 3, a diverse array of unprecedented transformations was investigated. We report novel crystallographically characterized products of successful nucleophilic/electrophilic addition and protonation/oxidation reactions.


General Considerations
All manipulations were carried out under an inert atmosphere using standard Schlenk and glovebox techniques, unless otherwise stated. Phosphorus trichloride, n-Butyllithium, triphenylmethane, 1,4diazabicyclo [2.2.2]octane, p-Toluenesulfonic acid monohydrate, iodomethane, tetrabromomethane and phenyldisulfide were purchased from commercial sources and used as supplied. Pinacolborane was purchased from commercial sources and distilled before use. LiCH2TMS was purchased from a commercial source as a solution in hexanes and was concentrated in vacuo to be used in a glovebox as a solid. [Fe(salen)]2-μ-oxo (1) was prepared via a literature procedure. [1] Pentane, diethyl ether, THF, and toluene were dried over sodium/benzophenone and distilled before use. Dichloromethane, dibromomethane and acetonitrile were dried over calcium hydride and distilled before use. NMR data was collected at 400 or 500 MHz on Bruker or Agilent instruments in C6D6/CD2Cl2/CDCl3/CD3CN/C7D8 at 298 K and referenced to residual protic solvent. Crystal structures were obtained from either a Rigaku Oxford Diffraction Xcalibur (MoKα (λ = 0.71073)) or Supernova (CuKα (λ = 1.54184)) diffractometer. HRMS analyses were performed using an Agilent QTOF 6545 with Jetstream ESI spray source coupled to an Agilent 1260 Infinity II Quat pump HPLC with 1260 autosampler, column oven compartment and variable wavelength detector (VWD). Melting point analyses were conducted on a Stuart SMP10 melting point apparatus. Infrared spectra were recorded at ambient temperature on a Perkin Elmer Spectrum 100 FT-IR spectrometer using a diamond ATR unit. Intensities are reported relative to the most intense signal as vw (very weak), w (weak), s (strong) or vs (very strong).

Starting Material and Substrate Syntheses Ph3CCH2Cl
Following a literature procedure, [2] n-Butyllithium (42.0 mmol, solution in hexanes) was added dropwise to a THF (100 mL) and diethyl ether (40 mL) solution of triphenylmethane (10.0 g, 40.9 mmol) at 0 °C before warming to room temperature and stirring for one hour. The resulting dark red solution was then transferred dropwise via cannula to a Schlenk flask containing DCM (100 mL). Any remaining precipitate was redissolved in THF and added to the DCM vessel. The resulting solution was stirred for one hour at room temperature before being quenched with water (100 mL). The organic layer was separated, and the aqueous layer extracted with ethyl acetate (2 x 25 mL) before the combined organic extracts were dried over magnesium sulphate. Filtration and removal of volatiles in vacuo yielded a dark red crude material. The crude product was crystallised from hot cyclohexane and washed with further cyclohexane to yield Ph3CCH2Cl as a white solid (6.25 g, 52%). . The values are in accordance to the literature. [2] Ph3CCH2PCl2 In an adaption of a literature procedure, [3] magnesium turnings (5.18 g, 213 mmol) were added to a Schlenk flask with a water-cooled reflux condenser attached. The magnesium turnings were flame-dried under vacuum, before being suspended in THF (20 mL). A small crystal of iodine was then added to activate the magnesium turnings, resulting in a brown suspension. The suspension was stirred at room temperature until the brown colour dissipated, before addition of a THF solution (20 mL) of Ph3CCH2Cl (6.25g, 21.3 mmol). The suspension was stirred at reflux for 6 hours to give a red solution before being cooled to room temperature. The Grignard reagent was then transferred via cannula filter to a THF solution (10 mL) of PCl3 (5.58 mL, 63.9 mmol) at -10 °C. The reaction was then allowed to warm to room temperature over 18 hours before removal of all volatiles in vacuo. The residue was then extracted with diethyl ether (3 x 20 mL) and filtered through a pad of celite. Volatiles were then removed in vacuo to give a solid yellow crude material. The crude product was crystallised from hot acetonitrile and washed with further acetonitrile to yield Ph3CCH2PCl2 as white crystals (3.2 g, 42%). 1 H NMR (500 MHz, 298 K, C6D6): δ 7.14 (d, 6H, J = 8.0 Hz, Ar-H) 7.03-6.98 (m, 6H, Ar-H), 6.97-6.93 (m, 3H, Ar-H), 3.80 (d, 2H, 2 JH-P = 3.9 Hz, CH2PCl2). 31 P{ 1 H} NMR (162 MHz, 298 K, C6D6): δ 185.6 (s). The values are in accordance to the literature. [3] Ph3CCP (2) In an adaptation of a literature procedure, [3] Ph3CCH2PCl2 (3.0 g, 8.35 mmol) was added to a Schlenk flask along with acetonitrile (50 mL). 1,4-diazabicyclo[2.2.2]octane (DABCO) (12.0 g, 107 mmol) and acetonitrile (40 mL) were added to a separate Schlenk flask and both vessels were heated to 75 °C until all material was dissolved. The DABCO solution was then added, in portions via cannula, to the solution of Ph3CCH2PCl2 at 75 °C over a 30 min period. Upon addition, a white vapour was observed, and the solution turned pale yellow. After complete addition, the solution was stirred for a further 4 h at 75 °C before being allowed to cool to room temperature. Volatiles were removed in vacuo, and toluene (50 mL) and an O2-free saturated NH4Cl aqueous solution (50 mL) were added. The toluene layer was extracted via cannula and the aqueous layer extracted with further toluene (2 x 20 mL). The organic extracts were then filtered through a pad of basic alumina, eluting with toluene (40 mL). The yellow solution was then concentrated in vacuo to give a tarry yellow solid. The solid was dissolved in a minimum amount of acetonitrile at 75 °C and left to warm to room temperature overnight. The resulting pale yellow crystals were washed with acetonitrile (2 x 5 mL) and dried under vacuo to give pure Ph3CCP (2) (1.42 g, 59%).  3 (s). The values are in accordance to the literature. [3] S4

Synthesis and Spectroscopic Data Scheme 2
Note on NMR spectra: Despite running 13 C{ 1 H} analysis on a spectrometer equipped with a cryoprobe, in multiple cases, quaternary carbon environments, especially those showing coupling to phosphorus environments, were poorly resolved/not observed. A previous reports of 3 gave similar observations for the quaternary -C=P, environments, where the C-P coupling could not be resolved. [4] In the case of 3', the sample was also very poorly soluble in a range on NMR solvents tested, and minimal signals in the 13 C{ 1 H} spectrum were observed despite multiple attempts at collecting better spectra. NMR spectra of 3'' and ClAu-3 were undertaken using CD2Cl2 contaminated with silicone grease carried through from solvent purification processes, hence high quantities are observed in the respective 1 H NMR spectra. This does not represent the purity of the prior-isolated crystalline solids. As mentioned above, 3' and 3'' only showed small amounts of solubility in CD2Cl2. Therefore, relative integrals of solvent impurities are not fully representative of the isolated product. Correction of yield via 1 H NMR spectroscopy is consequently not applicable in these cases.

3'
2,4,6-tris(triphenylmethyl)-Dewar-1,3,5-triphosphabenzene (0.2 mmol, 172 mg) was added to a J-Young's ampule along with toluene (2.5 mL). Lithium hexamethyldisilazane (66.96 mg, 0.4 mmol) was then added. The reaction was then heated to 110 °C, upon which the colour of the solution changed from orange to dark red. The reaction was left at this temperature for four days, and formation of an orange precipitate is observed. The precipitate was isolated by filtration and washed with toluene* (3 x 1 mL) before being dried in vacuo to give 3' as an orange-yellow solid (62 mg, 36%). *Prior to this, the crude precipitate was found to be insoluble in crystallisation attempts with benzene, toluene and THF (and only partially soluble in DCM), therefore the product was isolated by washing with toluene.

Synthesis and Spectroscopic Data for Gold Complexes
ClAu-3 2,4,6-tris(triphenylmethyl)-Dewar-1,3,5-triphosphabenzene (0.05 mmol, 43 mg) and chloro(dimethylsulfide)gold(I) (15 mg, 0.05 mmol) were added to a J-Young's NMR tube along with CD2Cl2 (0.6 mL). The reaction was left for 1 h at RT. Crystallisation via a dichloromethane/pentane vapour diffusion gives ClAu-3 as yellow crystals after 3 days (15 mg, 27%). 3' (0.006 mmol, 5 mg) and chloro(dimethylsulfide)gold(I) (1.8 mg, 0.006 mmol) were added to a J-Young's NMR tube along with CD2Cl2 (0.6 mL). The reaction was left for 1 h at RT. Analysis by 31 P NMR spectroscopy revealed complete conversion of 3' to new signals at δ 280.2 (d, 2P, 2 JP-P = 36.5 Hz, P b ) and 217.9 (t, 1P, 2 JP-P = 36.4 Hz, P a ) (see spectrum below). 95% conversion to ClAu-3' was calculated by 31 P NMR integrals. In comparison to the 31 P NMR signals of 3'' (δ 100.3 (d, 1 JP-P = 162.0 Hz, P b ), -80.8 (t, 1 JP-P = 162.0 Hz, P a ), the signal shifts observed suggest de-symmetrisation of the non-apical P b environments, alluding to coordination of AuCl at either one of these positions. This is supported by DFT, whereby coordination at the non-apical P site (P b ) is found to be energetically favourable relative to coordination at the apical site (P a ) (see computational SI). 31 P NMR (162 MHz, 298 K, CD2Cl2): S16 7. Synthesis and Characterisation Data Scheme 4 4a 2,4,6-tris(triphenylmethyl)-Dewar-1,3,5-triphosphabenzene (0.05 mmol, 43 mg) was added to a J-Young's NMR tube along with C6D6 (0.6 mL). Iodomethane (6.22 μL, 0.1 mmol) was then added. The reaction was then heated to 80 °C, upon which the colour of the solution changed from orange to dark red. The reaction was left at this temperature for 3 days, before being cooled to room temperature. Volatiles were removed in vacuo to give a dark red solid. The crude product was crystalised via a dichloromethane/pentane vapour diffusion to give 4a as red crystals (35 mg, 70%). S18 4b 2,4,6-tris(triphenylmethyl)-Dewar-1,3,5-triphosphabenzene (0.05 mmol, 43 mg) was added to a J-Young's NMR tube along with C6D6 (0.6 mL). Tetrabromomethane (24.9 mg, 0.075 mmol) was then added. The reaction was then heated to 80 °C, upon which the colour of the solution changed from orange to dark red. The reaction was left at this temperature for 1 hour, before being cooled to room temperature. Volatiles were removed in vacuo to give a dark red solid. The crude product was crystalised via a dichloromethane/pentane vapour diffusion to give 4b as red crystals (18 mg, 36%).  Phenylacetylene (109.8 μL, 1.0 mmol) was added to a small J-Young's Schlenk tube alongside THF (2 mL). The solution was cooled to -78 °C before n-butyllithium (0.44 mL, 2.5 M, 1.1 mmol) was added dropwise. The solution was stirred at this temperature for 30 mins, before being warmed to room temperature and stirred for a further 30 mins. A 100 μL aliquot of this reaction was taken and added to a J-Young's NMR tube containing 2,4,6-tris(triphenylmethyl)-Dewar-1,3,5-triphosphabenzene (0.05 mmol, 43 mg) and C6D6 (0.6 mL). An immediate dark purple colour change was observed. Characterised by in-situ NMR, not isolated. Spectroscopic yield: 77%. 2,4,6-tris(triphenylmethyl)-Dewar-1,3,5-triphosphabenzene (0.05 mmol, 43 mg) was added to a J-Young's NMR tube along with C6D6 (0.6 mL). p-Toluenesulfonic acid monohydrate (19 mg, 0.1 mmol) was then added. The reaction was then heated to 80 °C, upon which the colour of the solution changed from orange to yellow. The reaction was left at this temperature for 18 hours, before being cooled to room temperature. The reaction was filtered to remove any unreacted p-Toluenesulfonic acid monohydrate before the volatiles were removed in vacuo to give a yellow solid. The crude product was dissolved in a minimum amount of dichloromethane, and a few drops of pentane were added. The solution was left to crystallise overnight at -30 °C, giving 4b as pale yellow microcrystals (36 mg, 69%).   2,4,6-tris(triphenylmethyl)-Dewar-1,3,5-triphosphabenzene (0.05 mmol, 43 mg) was added to a J-Young's NMR tube along with C6D6 (0.6 mL). An excess of trifluoroacetic acid (16 μL, 0.2 mmol) was then added. The reaction was then heated to 80 °C, and the reaction was left at this temperature for 18 hours, before being cooled to room temperature. Volatiles were removed in vacuo to give a yellow solid. The crude product was crystalised via a dichloromethane/pentane vapour diffusion at -30 °C to give 4f as yellow crystals (13 mg, 27%). Each reaction was then monitored over 14 hours at room temperature, with 31 P NMR spectra recorded at ten minute intervals. The data was then processed and analysed by VTNA. [5][6] For 1, the best overlap is clearly found with half order. For 2, both half order and first order gave reasonable overlaps, therefore the reaction rate at each concentration of 2 was plotted against starting concentrations of 2, where a significantly better trend was found for first order with respect to 2.

VTNA graphs for order in 1:
First order

Reactions of 3 with NaHMDS and KHMDS
Reactions were set up between 3 and NaHMDS and KHMDS to see if isomerisation to 3' could also be facilitated by these salts. Conditions: 0.05 mmol 3, 0.1 mmol Na/KHMDS, 0.6 mL Tol-d8.
After 1 week at 110 °C, no change was observed in the 31 P NMR spectrum of the reaction with 3 and KHMDS. In the reaction with 3 and NaHMDS, conversion to 3' was observed after the same time and temperature. However, new signals relating to unknown impurities at 169.5 (br) and -17.2 ppm were also observed in the 31 P NMR spectrum (shown below).

Investigations into the Reactivity of 1 with Further Phosphaalkynes
Adamantylphosphaalkyne was synthesised from tris(trimethylsilyl)phosphine as per the method used by Becker and co-workers. [7] When implemented into the trimerisation conditions (0.5 mmol phosphaalkyne, 2 mol% 1, 0.5 eq. pinacolborane, 1:1 MeCN:Tol (0.6 mL), no conversion of adamantylphosphaalkyne was observed by 31 P NMR spectroscopy after 1 d at RT. A black precipitate had also formed, indicating that the iron catalysed had most likely decomposed. No further conversion was observed after further heating the reaction at 80 °C for 1 day.
Trimethylsilylphosphaalkyne was also synthesised via the method used by Russel and co-workers. [8] When implemented into the trimerisation conditions (1 mL of a 0.17 M stock solution of phosphaalkyne, 5 mol% 1, 0.5 eq. pinacolborane) no reaction was observed at RT or 50 °C via 31 P NMR analysis.
(2-pyridyl)3CH proved easily deprotonated by nBuLi, and the subsequent organolithium reagent was added to an excess of dichloromethane to yield full conversion to (2-pyridyl)3CCH2Cl after 42 h stirring at RT. The product was isolated via flash column chromatography (silica, 1 : 2 ethyl acetate : petroleum ether). Unfortunately, issues arose in completing the next step of the synthesis (addition to PCl3). Efforts to form the Grignard reagent of (2-pyridyl)3CCH2Cl were unsuccessful, despite activation of the magnesium turnings by flame-drying under vacuum, activation with iodine and refluxing the activated magnesium with the substrate in THF. We therefore sought to use a turbo-Grignard reagent, given their precedence for use in forming pyridyl-containing Grignard reagents. However, no reaction was observed between (2-pyridyl)3CCH2Cl and i PrMgCl·LiCl by 1 H NMR analysis at RT or 60 °C. A reaction with (2-pyridyl)3CCH2Cl with Li granules was also undertaken in hexane, again yielding no reaction after analysis by 1 H NMR spectroscopy. We then looked to replace the Cl moiety of (2-pyridyl)3CCH2Cl with a more reactive bromo-substituent. Repeating the synthesis of (2-pyridyl)3CCH2Cl with the use of dibromomethane instead of dichloromethane yielded pure (2-pyridyl)3CCH2Br after crystallisation from hot cyclohexane. Despite the more reactive bromo group, no reactivity was observed in reactions with activated magnesium, i PrMgCl·LiCl as well as a further reaction with sodium metal and a catalytic quantity of naphthalene each at reflux in THF. Full synthetic details and characterisations of (2pyridyl)3CCH2Cl and (2-pyridyl)3CCH2Br are given below.

(2-pyridyl)3CCH2Cl
(2-pyridyl)3CH [9] (1.07 g, 4.3 mmol) was added to a Schlenk flask along with THF (15 mL). The reaction was cooled to 0 °C before the dropwise addition of nBuLi (4.3 mmol), giving a red colour change. The reaction was warmed to RT and stirred for 1 h. The reaction mixture was then transferred dropwise via canula into another flask containing DCM (20 mL). The reaction was stirred at RT for 42 h until full conversion of starting material was observed via 1 H NMR analysis of a taken aliquot. The reaction was then quenched with de-ionised water (20 mL) and the organic layer was extracted and washed with further de-ionised water (2 x 20 mL). The organic layer was then dried over magnesium sulfate before being concentrated under vacuum, and the resulting crude product was purified by column chromatography (silica, 1 : 2 ethyl acetate : petroleum ether, ramping to 1 : 1) to yield (2-pyridyl)3CCH2Cl as a pale yellow oil which solidified overnight (0.89 g, 70%). (2-pyridyl)3CCH2Br (2-pyridyl)3CH [9] (1.28 g, 5.1 mmol) was added to a Schlenk flask along with THF (15 mL). The reaction was cooled to 0 °C before the dropwise addition of nBuLi (5.1 mmol), giving a red colour change. The reaction was warmed to RT and stirred for 1 h. The reaction mixture was then transferred dropwise via canula into another flask containing dibromomethane (20 mL). The reaction was stirred at RT for 1 h until full conversion of starting material was observed via 1 H NMR analysis of a taken aliquot. The reaction was then quenched with de-ionised water (20 mL) and the organic layer was extracted and washed with further de-ionised water (2 x 20 mL). The organic layer was then dried over magnesium sulfate before being concentrated under vacuum to give a red/brown crude oil. The resulting crude product was crystallized from hot cyclohexane to yield (2-pyridyl)3CCH2Br as orange crystals (1.29 g, 74%).

Crystallographic Information
Data for 3, 3'', ClAu-3, ClAu-3', 4a, 4c, 4e, and 4f were collected an Agilent SuperNova diffractometer (using a Cu-K radiation) while those for 4b were obtained using an Agilent Xcalibur instrument and an Mo-K source. All experiments were conducted at 150 K, solved using SHELXT [11] and refined using SHELXL [12] via the Olex-2 [13] interface. Noteworthy points in the individual X-ray diffraction experiments follow along with crystal structure and refinement details. Crystal structure data and refinement details are collated in Tables S2-S10 below. Comparisons of select bond distances/angles for solid-state structures 3, 4a, 4b, 4e and 4f are shown in Table S11. Solvent present in the structure of 3 appeared to be predominantly dichloromethane, but this is disordered with a small amount of pentane (20%). As such the lattice guests were treated with the solvent mask algorithm available in Olex-2, and an allowance of one molecule of dichloromethane per asymmetric unit made in the formula as presented.  Analysis of the raw diffraction frames pertaining to ClAu-3 revealed the presence of very minor crystal twinning. However, efforts to deconvolute this actually degraded the integrated data and were, thus, abandoned. The residual electron density maxima are chemically insignificant and are ripples in the region of the Au−Cl region. The asymmetric unit in this structure is also home to one molecule of dichloromethane. The motif in the structure of ClAu-3' contains an average of ClAu-3' (80%), 3'(20%) and a CH2Cl2 moiety with 15% occupancy. Distance and ADP restraints were employed in the solvent area, in order to achieve a chemically sensible convergence. Two molecules of dichloromethane in addition to one formula unit of the iodide salt comprise the asymmetric unit in the structure of 4a. The solvent molecule based on C62 was treated for 50:50 disorder, with the inclusion of ADP and distance restraints. The highest residual electron density peak lies 0.88 Å from I1 and, as such, is chemically insignificant The asymmetric unit in the structure of 4b comprises one molecule of the phosphorus containing complex and one molecule of dichloromethane. While disorder in the latter was not beyond modelling, the electron density remained somewhat smeared in that region of the difference Fourier electron density map. Thus, said solvent was ultimately treated using the Olex-2 solvent mask. The highest residual electron density peak lies 0.87 Å from Br2 and may even suggest some very minor disorder of this halide. However, efforts to model same rendered a disorder ratio of 98:2, and hence were not pursued. The structure of 4c was a challenge. The asymmetric unit in the structure of 4c comprises four molecules of the lithium based complex and a pool of toluene. Sample handling was exceedingly difficult because of the solvent content, as the crystals tended to crack and lose solvent once removed from the mother liquor leading to some degradation of the sample. Six of the toluene entities in the motif were order and included in the refinement while the remaining eleven were addressed using the SQUEEZE algorithm available in Platon. [14] This latter route was chosen in favour of inevitable, model over-parameterization that would have ensued with from the restraints and constraints needed to address extensive toluene disorder in the masked solvent regions of the electron-density map in the masked solvent regions of the electron-density map. Additionally, 50:50 disorder was accommodated in two of the target molecules in the structure, namely, the phenyl rings based on C11C and C36B. Distance and ADP restraints were employed, on merit, in disordered regions to assist convergence. Despite the challenges with sample handling, the experiment has rendered an unambiguous, solid-state characterisation of this compound. In compound 4e, the asymmetric unit was seen to contain one molecule of the phosphine complex, one molecule of p-toluenesulfonic acid and some solvent (dichloromethane). The latter was disordered in the main and was addressed using the solvent mask mentioned previously. Allowance has been made for two solvent molecules per asymmetric unit, in the formula as presented. H1 and H2 were located and refined without restraints. In the structure of 4f, the asymmetric unit is host to one molecule of the phosphorus containing species, an ordered molecule of dichloromethane and a disordered region of solvent that approximate to half of an additional CH2Cl2 entity. Disorder prevailed in the main feature, with the fluorine atoms each split over 2 sites in a 63:37 ratio and the phenyl ring based on C45 being modelled to take account of 83:17 disorder. This latter split of electron density impacted on the half-occupancy solvent moiety, to the extent that the associated (smeared) electron-density was ultimately treated using the Olex-2 solvent mask, with allowance being made for the squeezed solvent in the formula as presented. Distance and ADP restraints were employed, on merit, in disordered regions to assist convergence. The highest residual electron density peak is spurious.

Computational Methods
Optimizations of molecular geometries and Hessian calculations were carried out with the Gaussian 16 program [15] in conjunction with the SMD continuum solvent model [16] uitlizing acetonitrile as the solvent. The PBE0 [17,18] level of hybrid density functional theory (DFT) and the split-valence double-zeta def2-SVP [19] basis set were employed together with D3 atom-pairwise dispersion corrections including Becke-Johnson damping, [20][21][22][23][24] abbreviated PBE0-D3BJ(SMD)/def2-SVP. The 60 core electrons of Au were described by the quasi-relativistic effective core potential of Andrae et al. [25] Thermal contributions to enthalpies and Gibbs energies at 298.15 K were obtained at this level of DFT within the ideal gas, rigid-rotor, and harmonic oscillator approximations. All stationary points were characterized as minima or transition structures by eigenvalue analysis of the computed Hessians. Connections between transition states and the corresponding minima were confirmed by intrinsic reaction coordinate (IRC) calculations or by distortion of the transition state structures along the eigenvectors of imaginary frequency modes followed by unconstrained structure optimization. For all transition structures, additional broken-symmetry (BS) unrestricted Kohn-Sham (UKS) geometry optimizations were performed to obtain a molecular structure for these species, which were also used for subsequent single-point calculations. Singlet energies for these species were obtained after spin-projection according to Yamaguchi: [26][27][28] Single-point energy calculations with the triple-zeta def2-TZVP basis set [19] were employed for improved relative energies. The final Gibbs energies are thus obtained at the PBE0-D3BJ(SMD)/def2-TZVP // def2-SVP level.
The half-life t1 /2 of an intermediate was estimated from simple considerations according to the Eyring equation assuming first-order kinetics.